Primary arteriovenous fistula (AVF) failure, AVFs that are not suitable for dialysis at four to five months, remains the most significant obstacle in increasing overall prevalence of AVF use in the United States. There are currently no clinical or biological markers to predict which patients will experience primary AVF failure. The long-term goal of this project is to develop a panel of biomarkers from blood and venous tissue to better understand the mechanisms of primary AVF failure and that will serve as clinical tools to predict AVFs at high risk for maturation failures. The immediate objectives of this proposal focus on oxidative stress and pre-existing venous neointimal hyperplasia and will: (1) examine the relationship between pre-surgical levels of oxidative stress, pre-existing neointimal hyperplasia, and primary AVF failure, and (2) study the role of these novel risk factors in the pathophysiology of primary AVF failure. This study will utilize a prospective cohort study design recruiting chronic kidney and end-stage renal disease patients requiring a new AVF placement. Blood samples will be collected prior to surgery, and venous tissue samples will be collected at the time of surgery. Accomplishing these objectives will provide new information about the role blood and tissue oxidative stress levels and pre-existing neointimal hyperplasia play in primary AVF failure, and whether tissue oxidative stress is associated with pre-existing neointimal hyperplasia. Knowledge from this proposal will lead to future studies with targeted interventions directed at modifying oxidative stress and neointimal hyperplasia using both systemic and local delivery systems in order to improve AVF maturation. This research proposal will form the core of a five-year career development plan for Dr. Timmy Lee under the mentorship of Dr. Prabir Roy-Chaudhury, an internationally-recognized expert in hemodialysis vascular access stenosis. Dr. Lee proposes a career development plan that combines didactic training in translational research methods, advanced biostatistical coursework, and laboratory training related to understanding vascular access stenosis such as measurement of oxidative stress in blood and venous tissue and neointimal hyperplasia in human venous tissue. In conjunction with carefully selected collaborators, this career development plan will foster Dr. Lee's development into an established clinical and translational investigator with expertise in complex research methodology and laboratory expertise in mechanisms of vascular access stenosis. PUBLIC HEALTH RELEVANCE: Poor arteriovenous fistula development remains a significant problem among hemodialysis patients. The work from this proposal will improve the understanding of why some arteriovenous fistulas do not mature adequately for successful use on dialysis and which individuals are at risk for maturation failures. The net impact will, hopefully, be an improvement in patient quality of life and an overall increase in patient survival.